杏吧原创

ONCE, we could only marvel at the wonder of life. Like movie audiences not so long ago, we had little idea of what went on behind the scenes.

How times have changed. As the genomes of more and more species are sequenced, geneticists are piecing together an extraordinarily detailed 鈥淢aking of鈥︹�� documentary. Nowadays, we can not only trace how the bodies of animals have evolved, we can even identify the genetic mutations behind these changes.

Most intriguing of all, we can now see how genes 鈥� which are the recipes for making proteins, the building blocks of life 鈥� arise in the first place. And the story is not unfolding quite as expected.

鈥淲e can now see how genes arise in the first place. And the story is not unfolding quite as expected鈥�

The most obvious way for a new gene to evolve is through the gradual accumulation of small, beneficial mutations. Less obvious is how an existing gene that already does something important can evolve into a different gene. The scope for such a gene to change tack without capsizing the organism that carries it is very limited. However, as biologists , this constraint no longer applies when mutations produce an entire extra copy of a gene.

Trillions of copies

According to the textbooks, the process by which new genes form starts with gene duplication. In the vast majority of cases one of the copies will acquire harmful mutations and will be lost. Just occasionally, though, a mutation will allow a duplicate gene to do something novel. This copy will become specialised for its new role, while the original gene carries on performing the same task as before.

Surprisingly, gene duplication has turned out to be nearly as common as mutations that change a single 鈥渓etter鈥� of DNA code. During the exchange of material between chromosomes prior to sexual reproduction, mistakes can create extra copies of long DNA sequences containing anything from one gene to hundreds. Entire chromosomes can be duplicated, as happens in Down鈥檚 syndrome, and sometimes even entire genomes.

Since duplication can throw up trillions of copies for evolution to work with, it is not surprising that over hundreds of millions of years, a single original gene can give rise to many hundreds of new ones. We humans have around 400 genes alone, all of which derive from just two in a fish that lived around 450 million years ago.

Not the whole story

This classical view of gene evolution is far from the whole story, however. A decade ago, Michael Lynch at Indiana University in Bloomington and a colleague outlined an alternative scenario. Genes often have more than one function, and Lynch considered what might happen after such a gene is duplicated. If a mutation knocks out one of the two functions in one of the copies, an organism can cope fine because the other copy is still intact. Even if another mutation in this other copy knocks out the second function, the organism can carry on as normal. Instead of having one gene with two functions, the organism will now have two genes with one function each 鈥� a mechanism Lynch dubbed subfunctionalism (Genetics, vol 154, p 459). This process can provide the raw material for further evolution. 鈥淎 gene preserved by subfunctionalisation can later pick up a new function,鈥� Lynch says.

Some theoretical biologists think gene copies can also be preserved by other, more subtle, mechanisms, but the real challenge to the classical model comes from actual studies of new genes in various organisms. Earlier this year, in the most comprehensive study of its kind yet, a team led by Wen Wang of Kunming Institute of Zoology in Yunnan, China, looked at several closely related species of fruit fly. By comparing their genomes, Wang was able to identify new genes that have evolved in the 13 million years or so since these species split from a common ancestor.

One of Wang鈥檚 surprise discoveries was that around 10 per cent of the new genes had arisen through a process called retroposition. This occurs when messenger RNA copies of genes 鈥� the blueprints sent to a cell鈥檚 protein-making factories (see diagram) 鈥� are turned back into DNA that is then inserted somewhere else in the genome. Many viruses and genetic parasites copy themselves through retroposition, and the enzymes they produce sometimes accidentally retropose the RNA of their host cells.

Dead on arrival?

The gene copies created by retroposition are not the same as the original, as genes consist of more than just the sequence coding for a protein. There are also 鈥減romoter鈥� regions in the front of the coding part, to which other proteins bind, and this determines when and in which tissues the gene is turned on. Since retroposed gene copies lose their promoters, which are not transcribed into RNA, it used to be assumed that these partial copies were never expressed and gradually disappeared as mutations accumulated. Retroposed gene copies were dismissed as 鈥渄ead on arrival鈥�, says Henrik Kaessmann of the University of Lausanne, Switzerland.

However, it has become apparent that a retroposed copy can sometimes get inserted in the genome near an existing promoter, making it active. Crucially, though, with a different promoter, it will be turned on at different times or in different tissues or both. In this way a retroposed gene can immediately acquire a new function.

This process may have created many of the recently evolved genes in us apes. A burst of retroposition in our ancestors, peaking around 45 million years ago, gave rise to many thousands of gene duplicates, of which at least 60 or 70 evolved into new genes, according to led by Kaessmann. The burst was probably due to a new genetic parasite invading our genome.

Brainy genes

Kaessmann鈥檚 team is now studying some of these genes in more detail. Their work suggests that at least two, called and , could be related to apes鈥� increased cognitive abilities.

The evolution of new genes often involves even more drastic changes. In his fruit fly survey, Wang found that a third of new genes were significantly different from their parent genes, having lost parts of their sequences or acquired new stretches of DNA.

Where do these extra sequences come from? In complex cells, the DNA coding for a protein is broken into several parts, separated by non-coding sequences. After an RNA copy of the entire gene is made, the non-coding bits 鈥� the introns 鈥� are cut out and the coding parts 鈥� called exons 鈥� are spliced together. This edited RNA copy is then sent to a cell鈥檚 protein-making factory. The modular form of genes greatly increases the chances of mutations reshuffling existing genes and generating novel proteins. There are all sorts of ways in which it can happen: exons within a gene can be lost, duplicated or even combined with exons from different genes to create a new, chimeric gene.

Variations on a theme

For instance, most monkeys produce a protein called TRIM5, which protects them from infection by retroviruses. In one macaque in Asia around 10 million years ago, an inactive copy of a gene called CypA, produced by retroposition, was inserted near the TRIM5 gene. Further mutation resulted in cells producing a chimeric protein that was part TRIM5, part CypA. This protein provides better protection against some viruses. Although it might seem an unlikely series of events, in fact the TRIM5-CypA gene 鈥� much the same thing happened in owl monkeys in South America.

Given enough time 鈥� or rather enough mutations 鈥� gene duplication and reshuffling can produce new genes that are very different from the ancestral ones. But are all new genes variations on a theme, or can evolution throw up new genes unlike any that already exist?

A couple of decades ago, that unique genes could arise from what is called a frameshift mutation. Each amino acid in a protein is specified by three DNA 鈥渓etters鈥�, or bases 鈥� the triplet codon. If a mutation shifts the starting point for reading codons 鈥� the 鈥渞eading frame鈥� 鈥� by one base, or by two, the resulting protein sequence will be completely different. Since DNA is double-stranded, any given piece can be 鈥渞ead鈥� in six different ways.

Gibberish

The vast majority of mutations that alter the reading frame of a gene produce nonsense, usually dangerous nonsense. Many genetic diseases are the result of frameshift mutations wrecking proteins. It鈥檚 a bit like swapping every letter for the next one along in the alphabet: the result is usually gibberish.

But not always. In 2006, Stephen Scherer of the University of Toronto in Canada and his colleagues searched the human genome for new genes that had evolved by duplication followed by frameshift mutations affecting at least part of the original gene. They found 470 examples, suggesting that the process is surprisingly common ().

Another source of unique new genes could be the 鈥渏unk鈥� DNA littering most genomes. An early hint this might be so came a decade ago when a team at the University of Illinois revealed the genesis of the antifreeze protein produced by one Antarctic fish. The gene involved originally coded for a digestive enzyme. Then, around 10 million years ago, as the world鈥檚 climate cooled, part of one of the introns 鈥� a piece of junk DNA, in other words 鈥� got turned into an exon and subsequently duplicated many times, generating the characteristic repetitive structure of antifreeze proteins. From a random bit of DNA evolved a gene vital to the fish鈥檚 survival.

From scratch

Still, the antifreeze gene evolved from a pre-existing gene. What are the chances of mutations in junk DNA generating an entire new gene from scratch? Practically zero, most biologists thought until very recently. As Lynch points out, it takes a whole set of unlikely conditions for a piece of random DNA to evolve into a gene. First, some of the DNA must act as a promoter, telling the cell to make RNA copies of the rest. Next, these RNA copies must have a sequence that can be edited into a viable messenger RNA blueprint for the protein-making factories. What鈥檚 more, this messenger RNA must encode a relatively long protein 鈥� the average length is 300 amino acids 鈥� which is unlikely because in a random stretch of DNA, on average 1 in 20 every codons will be a 鈥渟top鈥� codon. Finally, of course, the new protein must do something useful. The obstacles seemed insurmountable.

Then, in 2006, David Begun of the University of California, Davis, and colleagues identified in fruit flies with sequences unlike any of the older genes. They that these genes, which code for relatively small proteins, have evolved from junk DNA in the past few million years. Begun quotes Sherlock Holmes: 鈥淲hen you have eliminated the impossible, whatever remains, however improbable, must be the truth.鈥�

Junk DNA

This year, during his hunt for new genes in fruit flies, Wang found another nine genes that appear to have evolved from scratch out of junk DNA. For eight of the nine, Wang has identified the non-coding sequences from which the genes evolved in related species, ruling out the possibility that these genes were somehow acquired ready-made from another organism.

Altogether, an astonishing 12 per cent of recently evolved genes in fruit flies . And Wang suspects this rate is low compared with other animals. 鈥淢y gut feeling is it may be higher in vertebrates because they have more junk DNA,鈥� he says.

It looks as if Wang could be right. A team at Trinity College Dublin in Ireland has found evidence that at least six new human genes have arisen from non-coding DNA in the 6 million years or so since humans and chimps diverged. The work is ongoing but the preliminary findings were presented at a meeting in Barcelona, Spain, in June. 鈥淲e鈥檙e very excited,鈥� says team leader Aoife McLysaght.

First hurdle

How can the number be so high when the likelihood of a gene evolving in this way is so rare? Part of the answer could be the recent discovery that even though at least half of our genome is junk, as much as 90 per cent of it can be accidentally transcribed into RNA on occasion. 鈥淭he first hurdle has already been overcome,鈥� McLysaght says.

This means it might not be that uncommon for random bits of junk DNA to get translated into a protein. Since most random proteins will probably be harmful, natural selection will eliminate these DNA sequences, but just occasionally one will strike it lucky, Begun says. A sequence that does something beneficial will spread through a population and rapidly evolve into a new gene, becoming optimised for whatever role it plays.

鈥淚t might not be that uncommon for random bits of junk DNA to get translated into a protein鈥�

It will be many years yet before we have a clear picture of the relative importance of the various mechanisms by which genes can evolve. What is certain, though, is that the classical view of how they evolve is far from complete. Evolution isn鈥檛 fussy 鈥� it鈥檒l take new genes wherever it can get them. 鈥淣atural selection is aggressively opportunistic,鈥� says Begun. 鈥淭he source of the raw material is irrelevant.鈥�

And as sequence data continues to pour in, biologists are well on their way to working out how every one of our 20,000 or so genes evolved. Better stock up on the popcorn and make sure your sofa is comfy: this is going to be one epic 鈥淢aking of鈥︹�� documentary.